This invention relates; to organic compounds, their preparation and their use as pharmaceuticals.
More particularly, the present invention relates to:
(a) compounds of formula 
xe2x80x83in free or salt form, where
X is an oxygen or sulfur atom or a group NR5,
R1 is an alkyl, alkenyl, cycloalkyl, benzocycloalkyl, cycloalkylalkyl or aralkyl group which optionally may be substituted by hydroxy, alkoxy, carboxy or alkoxycarbonyl or, when X is NR5, R1 may alternatively be a heterocyclyl group or a group of formula 
R2, R3, R4, R6, R7 and R8 are each independently hydrogen, halogen, alkyl, haloalkyl, alkoxy, carboxy, alkoxycarbonyl, carboxyalkyl, alkoxycarbonylalkyl, xe2x80x94N(R9)R10, xe2x80x94SO2N(R11)R12, C1-C4-alkylene-SO2N(R11)R12 or xe2x80x94CON(R13)R14 or, when two of R2, R3 and R4, or two of R6, R7 and R8, are attached to adjacent carbon atoms on the indicated benzene rings, they denote, together with the carbon atoms to which they are attached, a carbocyclic group having 5 to 10 ring atoms or a heterocyclic group having 5 to 10 ring atoms of which one, two or three are hetero atoms selected from nitrogen, oxygen and
R5 is hydrogen or alkyl,
R9 is hydrogen or alkyl and R10 is hydrogen, alkyl or xe2x80x94COR15 where R15 is alkyl, haloalkyl, alkoxy, alkoxyalkyl, alkoxycarbonyl, carboxyalkyl or alkoxycarbonylalkyl, or R9 and R10, together with the nitrogen atom to which they are attached, denote a heterocyclic group having 5 or 6 ring atoms of which one or two are hetero atoms selected from nitrogen, oxygen and sulfur,
R11 is hydrogen or alkyl and R12 is hydrogen, alkyl, hydroxyalkyl, alkoxyalkyl, carboxyalkyl or alkoxycarbonylalkyl, or R11 and R12 together with the nitrogen atom to which they are attached denote a heterocyclic group having 5 or 6 ring atoms of which one or two are hetero atoms selected from nitrogen, oxygen and sulfur, and
R13 and R14 are each independently hydrogen or alkyl; particularly to compounds of formula I in free or pharmaceutically acceptable salt form for use as pharmaceuticals; and
(b) compounds of formula I as hereinbefore defined in free or pharmaceutically acceptable salt form for use in the manufacture of medicaments for the treatment of conditions mediated by syk kinase.
In formula I, R9, R10, R11, R12, R13 or R14 in R2, R3 or R4 may be the same as, or may differ from, the respective group in R6, R7 or R8.
In another aspect, the present invention provides compounds of formula I as hereinbefore defined in free or salt form, with the exception of 2-(p-n-butylanilino)-6-methoxypurine, 2-(p-n-butylanilino)-6-(methylthio)purine, 2,6-di(phenylamino)purine, 2,6-di(p-tolylamino)purine, and 2-(p-tolylamino)-6-(phenylamino)purine.
In a further aspect, the present invention provides compounds of formula I as hereinbefore defined in free or salt form, with the exception of compounds of formula I where (i) X is oxygen or sulfur, R1 is alkyl, two of R2, R3 and R4 are hydrogen and one of R2, R3 and R4 is alkyl and (ii) X is NH, R1 is a group of formula II in which two of R6, R7 and R8 are hydrogen and the remaining one is hydrogen or alkyl, one of R2, R3, and R4 is hydrogen and the remaining two are each hydrogen or alkyl.
In a further aspect, the present invention provides a compound of formula I as hereinbefore described in free or salt form in which
(a) X is NR5 and R1, R2, R3, R4 and R5 are as hereinbefore defined, with the proviso that when R1 is a group of formula II, R6, R7 and R8 are each independently halogen, haloalkyl, alkoxy, carboxy, alkoxycarbonyl, carboxyalkyl, alkoxycarbonylalkyl, xe2x80x94N(R9)R10, xe2x80x94SO2N(R11)R12, C1-C4-alkylene-SO2N(R11)R12 or xe2x80x94CON(R13)R14 or, when two of R6, R7 and R8 are attached to adjacent carbon atoms on the indicated benzene ring, they denote, together with the carbon atoms to which they are attached, a carbocyclic group having 5 to 10 ring atoms or a heterocyclic group having 5 to 10 ring atoms of which one, two or three are hetero atoms selected from nitrogen, oxygen and sulfur, or one or two of R6, R7 and R8 are hydrogen; or
(b) X is oxygen or sulfur and R1, R2, R3 and R4 are as hereinbefore defined, with the proviso that when R1 is alkyl, R2, R3and R4 are each independently hydrogen, halogen, alkoxy, carboxy, alkoxycarbonyl, carboxyalkyl, alkoxycarbonylalkyl, xe2x80x94N(R9)R10, xe2x80x94SO2N(R11)R12, C1-C4-alkylene-SO2N(R11)R12 or xe2x80x94CON(R13)R14 or, when two of R2, R3 and R4 are attached to adjacent carbon atoms on the indicated benzene rings, they denote, together with the carbon atoms to which they are attached, a carbocyclic group having 5 to 10 ring atoms or a heterocyclic group having 5 to 10 ring atoms of which one, two or three are hetero atoms selected from nitrogen, oxygen and sulfur.
Terms used in this specification have the following meanings:
xe2x80x9cAlkylxe2x80x9d denotes straight chain or branched alkyl, which may be, for example, C1 to C10-alkyl such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, straight or branched pentyl, straight or branched hexyl, straight or branched heptyl, straight or branched nonyl or straight or branched decyl. Preferably alkyl is C1 to C4-alkyl.
xe2x80x9cAlkoxyxe2x80x9d denotes straight chain or branched alkoxy and may be, for example, C1 to C10 alkoxy such as methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy, tert-butoxy, or straight or branched pentoxy, hexyloxy, heptyloxy, octyloxy, nonyloxy or decyloxy. Preferably alkoxy is C1 to C4-alkoxy.
xe2x80x9cAlkenylxe2x80x9d means straight chain or branched alkenyl, which may be, for example, C2 to C10-alkenyl such as vinyl, 1-propenyl, 2-propenyl, 1-butenyl, isobutenyl, or straight or branched pentenyl, hexenyl, heptenyl, octenyl, nonenyl or decenyl. Preferred alkenyl is C2 to C4-alkenyl.
xe2x80x9cCycloalkylxe2x80x9d means C3 to C10-cycloalkyl having 3 to 8 ring carbon atoms and may be, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl or cycloheptyl, any of which can be substituted by one, two or more C1-C4 alkyl groups, particularly methyl groups. Preferably, cycloalkyl is C3-C6-cycloalkyl.
xe2x80x9cBenzocycloalkylxe2x80x9d means cycloalkyl, e.g. one of the C3 to C10 cycloalkyl groups mentioned hereinbefore, attached at two adjacent carbon atoms to a benzene ring. Preferably, benzocycloalkyl is benzo-C5-C6-cycloalkyl, especially benzocyclohexyl (tetrahydronaphthyl).
xe2x80x9cCycloalkylalkylxe2x80x9d means C3 to C10-cycloalkyl xe2x80x94C1-C10 alkyl where the C3 to C10-cyloalkyl group has 3 to 8 ring carbon atoms and may be, for example, one of the C1-C10-alkyl groups mentioned hereinbefore, particularly one of the C1-C4-alkyl groups, substituted by one of the C3-C10-cycloalkyl groups mentioned hereinbefore. Preferably cycloalkylalkyl is C3-C6-cycloalkyl-C1-C4-alkyl.
xe2x80x9cAralkylxe2x80x9d means C6-C10-aryl-C1-C10 alkyl and may be, for example, one of the C1-C10-alkyl groups mentioned hereinbefore, particularly one of the C1-C4-alkyl groups, substituted by phenyl, tolyl, xylyl or naphthyl. Preferably, aralkyl is phenyl-C1-C4-alkyl, particularly benzyl or 2-phenylethyl.
xe2x80x9cHeterocyclylxe2x80x9d means a monovalent heterocyclic radical having up to 20 carbon atoms and one, two, three or four heteroatoms selected from nitrogen, oxygen and sulfur, the radical optionally having an alkyl, alkylcarbonyl, hydroxyalkyl, alkoxyalkyl or aralkyl group attached to a ring carbon or nitrogen atom and being linked to the remainder of the molecule through a ring carbon atom, and may be, for example, a radical, preferably a monocyclic radical, with one nitrogen, oxygen or sulfur atom such as pyrryl, pyridyl, piperidyl, furyl, tetrahydrofuryl or thienyl, or a radical, preferably a monocyclic radical, with two hetero atoms selected from nitrogen, oxygen and sulfur, such as imidazolyl, pyrimidinyl, piperazinyl, oxazolyl, isoxazolyl, thiazolyl, morpholinyl or thiomorpholinyl. Preferably, heterocyclyl is a monocyclic radical having 5 or 6 ring atoms and one or two nitrogen atoms, or one nitrogen atom and one oxygen atom, in the ring and optionally substituted on a ring nitrogen atom by C1-C4-alkyl, hydroxy-C1-C4-alkyl, C1-C4-alkylcarbonyl or phenyl-C1-C4-alkyl.
xe2x80x9cAlkoxyalkylxe2x80x9d means straight chain or branched alkyl substituted by one or more alkoxy groups and may be, for example, a C1-C10-alkoxy-C1-C10-alkyl group, such as one of the C1-C10-alkyl groups, particularly one of the C1-C4-alkyl groups, mentioned hereinbefore substituted by one of the C1-C10-alkoxy groups, preferably one of the C1-C4-alkoxy groups, mentioned hereinbefore. Preferably alkoxyalkyl is C1-C4-alkoxy-C1-C4 alkyl.
xe2x80x9cCarboxyalkylxe2x80x9d means straight chain or branched alkyl, for example C1-C10-alkyl such as one of the C1-C10-alkyl groups mentioned hereinbefore, substituted, preferably on a primary carbon atom, by a carboxyl group. Preferably carboxyalkyl is carboxy-C1-C4-alkyl.
xe2x80x9cAlkylcarbonylxe2x80x9d means a group R16CO where R16 is alkyl, for example C1-C10-alkyl such as one of the C1-C10-, preferably C1-C4-, alkyl groups mentioned hereinbefore. Preferably, alkylcarbonyl is C1-C4-alkylcarbonyl, i.e. R16CO where R16 is C1-C4-alkyl.
xe2x80x9cAlkoxycarbonylxe2x80x9d means a group R17CO where R17 is an alkoxy group, for example a C1-C10 alkoxy group such as one of the C1-C10, preferably C1-C4, alkoxy groups mentioned hereinbefore. Preferably, alkoxycarbonyl is C1-C4-alkoxycarbonyl, i.e. R17CO where R17 is C1-C4-alkoxy.
xe2x80x9cAlkoxycarbonylalkylxe2x80x9d means straight or branched chain alkyl, for example a C1-C10 alkyl group such as one of the C1-C10-, preferably C1-C4-, alkyl groups mentioned hereinbefore, substituted by an alkoxycarbonyl group as hereinbefore defined. Preferably, alkoxycarbonylalkyl is C1-C4-alkoxy-carbonyl-C1-C4-alkyl.
xe2x80x9cHaloalkylxe2x80x9d means straight chain or branched alkyl, for example C1-C10-alkyl such as one of the C1-C10-alkyl groups mentioned hereinbefore, substituted by one or more, for example one, two or three, halogen atoms, preferably fluorine or chlorine atoms. Preferably haloalkyl is C1-C4-alkyl substituted by one, two or three fluorine or chlorine atoms.
xe2x80x9cHydroxyalkylxe2x80x9d means straight chain or branched alkyl, for example C1-C10-alkyl such as one of the C1-C10-alkyl groups mentioned hereinbefore, substituted by one, two or three hydroxyl groups. Preferably, hydroxyalkyl is C1-C4-alkyl substituted by one hydroxyl group.
Where one of R2, R3 and R4, or one of R6, R7 and R8, is hydrogen and the second and third of R2, R3 and R4, or the second and third of R6, R7 and R8, are attached to adjacent carbon atoms in the respective benzene ring and together with said adjacent carbon atoms denote a carbocyclic group or heterocyclic group, the second and third of R2, R3 and R4, or the second and third of R6, R7 and R8, may denote, together with the benzene ring to which they are attached, a C9-C15-carbocyclic group such as indenyl or naphthyl, optionally substituted by one or more C1-C4-alkyl or C1-C4-alkoxy groups, dihydronaphthyl, tetrahydronaphthyl, fluorenyl, anthryl or phenanthryl, preferably a C10-C15-carbocyclic aromatic group or tetrahydronaphthyl; or the second and third of R2, R3 and R4, or the second and third of R6, R7 and R8, may denote, together with the benzene ring to which they are attached, a heterocyclic group having 9 to 14 ring atoms, of which one, two or three are heteroatoms selected from nitrogen, oxygen and sulfur, for example an indolyl, benzimidazolyl, indazolyl or carbazolyl group (which is optionally substituted on a nitrogen atom by C1-C4-alkyl, hydroxy-C1-C4-alkyl or phenyl-C1-C4-alkyl), or benzofuranyl, benzothiophenyl, qunolinyl, isoquinolinyl, naphthyridinyl, dioxanapthyl (benzodioxanyl), benzoxazolyl, benzothiazolyl, benzofuranonyl or benzofurazanyl, preferably a heterocyclic group having 9 to 13 ring atoms, of which one or two are hetero atoms selected from nitrogen, oxygen and sulfur.
Where R9 and R10, or R11 and R12, together with the nitrogen atom to which they are attached, denote a heterocyclic group, the heterocyclic group may be, for example, a group having one or two nitrogen atoms in the ring such as a pyrrolidinyl, imidazolyl, imidazolidinyl, piperidyl or piperazinyl group, the group having two nitrogen atoms in the ring being optionally substituted on the second nitrogen atom by a C1-C4-alkyl, hydroxy-C1-C4-alkyl, C1-C4-alkylcarbonyl, a C1-C4-alkoxycarbonyl or phenyl-C1-C4-alkyl group, or the heterocyclic group may be a group having one nitrogen atom and one oxygen atom in the ring, such as a tetrahydro-oxazolyl, tetrahydro-isoxazolyl or mopholino group, which may be substituted on one or more ring carbon atoms by a C1-C4-alkyl group.
Preferred compounds of formula I and their salts are compounds of formula 
in free or salt form, where
R1 is as hereinbefore and, when it is a group of formula II, it is a group of formula 
and R2, R3, R4, R6, R7 and R8 are as hereinbefore defined.
Preferably, in formula I and formula III, R1 is a C1-C10-alkyl, especially C1-C4-alkyl, C2-C10-alkenyl, especially C2-C4-alkenyl, C3-C10-cycloalkyl, especially C3-C6-cycloalkyl, benz-C3-C10-cycloalkyl, especially benzo-C5-C6-cycloalkyl, phenyl-C1-C10-alkyl, especially phenyl-C1-C4-alkyl, or C3-C10-cycloalkyl-C1-C4-alkyl, especially C3-C6-cycloalkyl-C1-C4-alkyl, group which is optionally substituted by a hydroxy, carboxy or C1-C4-alkoxycarbonyl group, or R1 is a heterocyclyl radical having 5 or 6 ring atoms and one or two nitrogen atoms, or one nitrogen atom and one oxygen atom, in the ring and optionally substituted on a ring nitrogen atom by C1-C4-alkyl, hydroxy-C1-C4-alkyl, C1-C4-alkylcarbonyl or phenyl-C1-C4-alkyl, or
R1 is a group of formula II or formula IV respectively in which one of R6, R7 and R8 is hydrogen, C1-C4-alkyl or C1-C4-alkoxy, and (i) the second and third of R6, R7 and R8 are each independently hydrogen, C1-C4-alkyl or C1-C4-alkoxy or (ii) the second of R6, R7 and R8 is hydrogen and the third of R6, R7 and R8 is carboxy, C1-C10-, preferably C1-C4-alkoxycarbonyl, carboxy C1-C10-, preferably carboxy-C1-C4-alkyl, C1-C10-alkoxycarbonyl-C1-C10-alkyl, preferably C1-C4-alkoxycarbonyl-C1-C4-alkyl, xe2x80x94N(R9)R10, xe2x80x94SO2N(R11)R12, C1-C4-alkylene-SO2N(R11)R12 or xe2x80x94CON(R13)R14, or (iii) the second and third of R6, R7 and R8 are attached to adjacent carbon atoms in the indicated benzene ring and, together with said adjacent carbon atoms, denote a carbocyclic group having 5 or 6 ring atoms or a monocyclic heterocyclic group having 5 or 6 ring atoms and one or two nitrogen atoms in the ring,
one of R2, R3 and R4 is hydrogen, C1-C4-alkyl or C1-C4-alkoxy and (a) the second and third of R2, R3 and R4 are each independently hydrogen, C1-C4-alkyl or C1-C4-alkoxy, or (b) the second of R2, R3 and R4 is hydrogen and the third of R2, R3 and R4 is carboxy, C1‥C10, preferably C1-C4-, alkoxycarbonyl, carboxy-C1-C10-oalkyl, preferably carboxy-C1-C4-alkyl, C1-C10-alkoxycarbonyl-C1-C10-alkyl, preferably C1-C4-alkoxycarbonyl-C1-C4-alkyl, xe2x80x94N(R9)R10, xe2x80x94SO2N(R11)R12, C1-C4-alkylene-SO2N(R11)R12 or xe2x80x94CON(R13)R4, or (c) the second and third of R2, R3 and R4 are attached to adjacent carbon atoms in the indicated benzene ring and, together with said adjacent carbon atoms, denote a carbocyclic group having 5 or 6 ring atoms or a heterocyclic group having 5 to 10 ring atoms, of which one or two are hetero atoms selected from nitrogen, oxygen and sulfur,
R9 is hydrogen or C1-C10-, preferably C1-C4-, alkyl and R10 is hydrogen, C1-C10-, preferably C1-C4-, alkyl, or xe2x80x94COR15 where R15 is C1-C10-, preferably C1-C4-, alkyl, C1-C10-haloalkyl, preferably C1-C4-haloalkyl, C1-C10-alkoxy-C1-C10-alkyl, preferably C1-C4-alkoxy- C1-C4-alkyl, C1-C10-alkoxycarbonyl, preferably C1-C4-alkoxycarbonyl, carboxy-C1-C10-alkyl, preferably carboxy-C1-C4-alkyl, or C1-C10-alkoxycarbonyl-C1--C10 alkyl, preferably C1-C4-alkoxycarbonyl-C1-C4-alkyl, or R9 and R10 together with the nitrogen atom to which they are attached, denote a heterocyclic group having 5 or 6 ring atoms and one or two nitrogen atoms, or one nitrogen atom and one oxygen atom, in the ring,
R11 is hydrogen or C1-C10-, preferably C1-C4-, alkyl and R12 is hydrogen, C1-C10-, preferably C1-C4-, alkyl, hydroxy-C1-C10-alkyl, preferably hydroxy-C1-C4-alkyl, C1-C10-alkoxy-C1-C10-alkyl, preferably C1-C4-alkoxy-C1-C4-alkyl, carboxy-C1-C10-alkyl, preferably carboxy-C1-C4-alkyl, or C1-C10-alkoxycarbonyl-C1-C10-alkyl, preferably C1-C4-alkoxycarbonyl-C1-C4-alkyl, or R11 and R12 together with the nitrogen atom to which they are attached denote a heterocyclic group having 5 or 6 ring atoms and one or two nitrogen atoms, or one nitrogen atom and one oxygen atom, in the ring, and R13 and R14 are each independently hydrogen or C1-C10-, preferably C1-C4-, alkyl.
Preferred compounds of formula I or III and their salts include those in which:
X is a group NR5,
R1 is a C1-C4-alkyl, C2-C4-alkenyl, C3-C5 cycloalkyl, benzo-C5-C6-cycloalkyl, phenyl-C1-C4-alkyl or C3C5 cycloalkyl-C1-C4-alkyl group, which is optionally substituted by a hydroxy, carboxy or C1-C4-alkoxycarbonyl group, or R1 is a heterocyclyl radical having 5 or 6 ring atoms and one or two nitrogen atoms, or one nitrogen atom and one oxygen atom, in the ring and optionally substituted on a ring nitrogen atom by C1-C4 alkyl, C1-C4-hydroxyalkyl, C1-C4-alkylcarbonyl or phenyl-C1-C4-alkyl, or R1 is a group of formula IV in which one of R6, R7 and R8 is hydrogen, C1-C4-alkyl or alkoxy, and (i) the second and third of R6, R7 and R8 are each independently hydrogen, C1-C4-alkyl or C1-C4-alkoxy or (ii) the second of R6, R7 and R8 is hydrogen and the third of R6, R7 and R8 is xe2x80x94N(R9)R10, xe2x80x94SO2N(R11)R12 or xe2x80x94CON(R13)R14, or (iii) the second and third of R6, R7 and R8 are attached to adjacent carbon atoms in the indicated benzene ring and together with said adjacent carbon atoms denote a carbocyclic group having 5 or 6 ring atoms or a heterocyclic group having 5 or 6 ring atoms, of which one or two are nitrogen atoms, one of R2, R3 and R4 is hydrogen, C1-C4-alkyl or C1-C4-alkoxy and (a) the second and third of R2, R3 and R4 are each independently hydrogen, C1-C4-alkyl or C1-C4-alkoxy or (b) the second of R2, R3 and R4 is hydrogen and the third of R2, R3 and R4 is carboxy, C1-C4-alkoxycarbonyl, carboxy-C1-C4-alkyl, C1-C4-alkoxycarbonyl-C1-C4-alkyl, xe2x80x94N(R9)R10, xe2x80x94SO2N(R11)R12, C1-C4-alkylene-SO2N(R11)R12 or xe2x80x94CON(R13)R14, or (c) the second and third of R2, R3 and R4 are attached to adjacent carbon atoms in the indicated benzene ring and denote, together with said adjacent carbon atoms, a heterocyclic group having 5 to 10 ring atoms, of which one or two are hetero atoms selected from nitrogen, oxygen and sulfur,
R5 is hydrogen or C1-C4-alkyl,
R9 is hydrogen or C1-C4 alkyl and R10 is hydrogen, C1-C4 alkyl, or xe2x80x94COR15 where R15 is C1-C4-alkyl, C1-C4-haloalkyl, C1-C4-alkoxy, C1-C4-alkoxy-C1-C4 alkyl, C1-C4-alkoxycarbonyl, or C1-C4-alkoxycarbonyl-C1-C4-alkyl, or R9 and R10 together with the nitrogen atom to which they are attached denote a heterocyclic group having 5 or 6 ring atoms including one or two ring nitrogen atoms, or one nitrogen ring atom and one oxygen ring atom, R11 is hydrogen or C1-C4-alkyl and R12 is hydrogen, C1-C4-alkyl, hydroxy-C1-C4-alkyl, C1-C4-alkoxy-C1-C4-alkyl or C1-C4-alkoxycarbonyl-C1-C4-alkyl, or R11 and R12 together with the nitrogen atom to which they are attached denote a heterocyclic group having 5 or 6 ring atoms including one or two ring nitrogen atoms, or one nitrogen ring atom and one oxygen ring atom, and
R13 and R14 are each independently hydrogen or C1-C4-alkyl.
Further preferred amongst the above mentioned compounds where X is a group NR5 are those where
R1 is C1-C4-alkyl which is optionally substituted by hydroxy, C2-C4-alkenyl, C3-C5-cycloalkyl which is optionally substituted by carboxy or C1-C4-alkoxycarbonyl, benzo-C5-C6-cycloalkyl, phenyl-C1-C4-alkyl optionally substituted by hydroxy, C3-C5-cycloalkyl-C1-C4-alkyl, a heterocyclyl radical having 6 ring atoms and one or two nitrogen atoms in the ring optionally substituted on a ring nitrogen atom by phenyl-C1-C4-alkyl, or a group of formula IV in which one of R6, R7 and R8 is hydrogen, C1-C4-alkyl or C1-C4-alkoxy, and (i) the second and third of R6, R7 and R8 are each hydrogen or (ii) the second of R6, R7 and R8 is hydrogen and the third of R6, R7 and R8 is xe2x80x94N(R9)R10 where R9 is hydrogen or C1-C4-alkyl and R10 is xe2x80x94COR15 where R15 is C1-C4-alkyl, C1-C4-alkoxy, xe2x80x94SO2N(R11)R12 where R11 and R12 are each hydrogen, C1-C4-alkyl, or xe2x80x94CON(R13)R14 where R13 and R14 are each hydrogen, or (iii) the second and third of R6, R7 and R8 are attached to adjacent carbon atoms in the indicated benzene ring and denote, together with said adjacent carbon atoms, a carbocyclic group having 6 ring atoms or a heterocyclic group having 5 ring atoms, of which two are nitrogen atoms,
one of R2, R3 and R4 is hydrogen, C1-C4-alkyl or C1-C4-alkoxy, and (a) the second and third of R2, R3 and R4 are each independently hydrogen or C1-C4-alkoxy or (b) the second of R2, R3 and R4 is hydrogen and the third of R2, R3 and R4 is carboxy, C1-C4-alkoxycarbonyl, carboxy-C1-C4-alkyl, C1-C4-alkoxycarbonyl-C1-C4-alkyl, xe2x80x94N(R9)R10 where R9 is hydrogen or C1-C4-alkyl and R10 is hydrogen, C1-C4-alkyl, or xe2x80x94COR15 where R15 is C1-C4-alkyl, C1-C4-haloalkyl, C1-C4-alkoxy, C1-C4-alkoxy-C1-C4-alkyl, C1-C4-alkoxycarbonyl or C1-C4-alkoxycarbonyl-C1-C4-alkyl, or R9 and R10 together with the nitrogen atom to which they are attached denote a heterocyclic group having 5 or 6 ring atoms including one or two ring nitrogen atoms, preferably piperazinyl, piperidino, pyrrolidonyl, or one ring nitrogen atom and one ring oxygen atom, preferably morpholino, the heterocyclic group having two ring nitrogen atoms optionally having a C1-C4-alkyl, a hydroxy C1-C4-alkyl, a C1-C4-alkylcarbonyl, a C1-C4-alkoxycarbonyl or C1-C4-alkoxycarbonylalkyl group attached to the nitrogen atom in the xe2x80x94R9xe2x80x94R10- radical, and the heterocyclic group having one ring nitrogen atom and one ring oxygen atom optionally having one or two C1-C4-alkyl groups attached to a ring carbon atom, or the third of R2, R3 and R4 is xe2x80x94SO2N(R11)R12 where R11 is hydrogen or C1-C4-alkyl and R12 is hydrogen, C1-C4-alkyl, hydroxy-C1-C4-alkyl, C1-C4-alkoxy-C1-C4-alkyl or C1-C4-alkoxycarbonyl-C1-C4-alkyl, or R11 and R12 together with the nitrogen atom to which they are attached denote a heterocyclic group having 6 ring atoms including one or two ring nitrogen atoms, e.g. piperidino or piperazinyl, or one ring nitrogen atom and one ring oxygen atom, e.g. morpholino, the heterocyclic group having two ring nitrogen atoms optionally having a C1-C4-alkyl group attached to the nitrogen atom in the xe2x80x94R11xe2x80x94R12- radical, or the third of R2, R3 and R4 is C1-C4-alkylene-SO2N(R11)R12 where R11 and R12 are each independently hydrogen or C1-C4-alkyl, or the third of R2, R3 and R4 is xe2x80x94CON(R13)R14 where R13 and R14 are each independently hydrogen or C1-C4-alkyl, or (c) the second and third of R2, R3 and R4 are attached to adjacent carbon atoms in the indicated benzene ring and denote, together with said adjacent carbon atoms, a heterocyclic group having 5 to 9 ring atoms, of which one or two are hetero atoms selected from nitrogen, oxygen and sulfur, especially an indazolyl, benzothiazolyl, quinolyl, indolyl, benzofuranonyl or dioxanaphthyl group, and
R5 is hydrogen or C1-C4-alkyl.
Other preferred compounds of formula I or III and their salts are those where X is an oxygen atom, R1 is C1-C4-alkyl or C3-C10 cycloalkyl, one of R2, R3 and R4 is hydrogen, and either (i) the second of R2, R3 and R4 is hydrogen and the third of R2, R3 and R4 is carboxy, C1-C4-alkoxycarbonyl or xe2x80x94N(R9)R10 where R9 and R10 together with the attached nitrogen atom denote a heterocyclic group having 5 or 6 ring atoms including two ring nitrogen atoms or one ring nitrogen atom and one ring oxygen atom, or (ii) the second and third of R2, R3 and R4 are attached to adjacent carbon atoms on the indicated benzene ring and together with the carbon atoms to which they are attached denote a heterocyclic group having 5 or 6 ring atoms, of which one or two are nitrogen atoms.
Further preferred amongst the compounds of formula I or III and their salts where X is an oxygen atom are those where R1 is C1-C4-alkyl or C3-C5cycloalkyl, one of R2, R3 and R4 is hydrogen and either (a) the second of R2, R3 and R4 is hydrogen and the third of R2, R3 and R4 is carboxy, C1-C4-alkoxycarbonyl or xe2x80x94N(R9)R10 where R9 and R10 together with the attached nitrogen atom denote a heterocyclic group having 6 ring atoms including one ring nitrogen atom and one ring oxygen atom, or (b) the second and third of R2, R3 and R4 are attached to adjacent carbon atoms on the indicated benzene ring and denote, together with said adjacent carbon atoms, a heterocyclic group having 5 ring atoms, of which two are nitrogen atoms.
Another group of preferred compounds of formula I or III and their salts are those where X is a sulfur atom, R1 is C1-C4-alkyl, two of R2, R3 and R4 are hydrogen and the third of R2, R3 and R4 is carboxy, C1-C4-alkoxycarbonyl, or xe2x80x94N(R9)R10 where R9 is hydrogen or C1-C4-alkyl and R10 is xe2x80x94COR15 where R15 is C1-C4-alkyl, or R9 and R10 together with the nitrogen atom to which they are attached denote a heterocyclic group having 5 or 6 ring atoms induding one or two ring nitrogen atoms or one ring nitrogen atom and one ring oxygen atom, preferably a heterocyclic group having 6 ring atoms including one ring nitrogen atom and one ring oxygen atom.
The compounds represented by formula I are capable of forming acid addition salts, particularly pharmaceutically acceptable acid addition salts. Pharmaceutically acceptable acid addition salts of the compound of formula I include those of inorganic acids, for example, hydrohalic acids such as hydrofluoric acid, hydrochloric acid, hydrobromic acid or hydriodic acid, nitric acid, sulfuric acid, phosphoric acid; and organic acids, for example aliphatic monocarboxylic acids such as formic acid, acetic acid, trifluoroacetic acid, propionic acid and butyric acid, aliphatic hydroxy acids such as lactic acid, citric acid, tartaric acid or malic acid, dicarboxylic acids such as maleic acid or succinic acid, aromatic carboxylic acids such as benzoic acid, p-chlorobenzoic acid, diphenylacetic acid or triphenylacetic acid, aromatic hydroxy acids such as o-hydroxybenzoic acid, p-hydroxybenzoic acid, 1-hydroxynaphthalene-2-carboxylic acid or 3-hydroxynaphthalene-2-carboxylic acid, and sulfonic acids such as methanesulfonic acid or benzenesulfonic acid. These salts may be prepared from compounds of formula I by known salt-forming procedures.
Compounds of formula I which contain acidic, e.g. carboxyl, groups, are also capable of forming salts with bases, in particular pharmaceutically acceptable bases such as those well known in the art; suitable such salts include metal salts, particularly alkali metal or alkaline earth metal salts such as sodium, potassium, magnesium or calcium salts, or salts with ammonia or pharmaceutically acceptable organic amines or heterocyclic bases such as ethanolaniines, benzylamines or pyridine. These salts may be prepared from compounds of formula I by known salt-forming procedures.
Specific especially preferred compounds of the invention are those described hereinafter in the Examples. Among these, most preferred compounds include those of formula III in which
(i) X is NH, R1 is cyclopropyl, R2 and R4 are each hydrogen and R3 is NHCOOC(CH3)3; or
(ii) X is NH, R1 is cyclopropyl, R2 and R4 are each hydrogen and R3 is morpholino; or
(iii) X is NH, R1 is cyclobutyl, R2 and R4 are each hydrogen and R3 is 4tert-butoxycarbonyl-1-piperazinyl; or
(iv) X is NH, R1 is cyclobutyl, R2 and R4 are each hydrogen and R3 is xe2x80x94N(CH3)COCH3; or
(v) X is NH, R1 is isopropyl, R2 and R4 are each hydrogen and R3 is xe2x80x94SO2N(CH3)2; or
(vi) X is NH, R1 is cyclopropyl, R2 and R4 are each hydrogen and R3 is 4-acetyl-1-pipcrazinyl; or
(vii) X is NH, R1 is tert-butyl, R2 is hydrogen and R3 and R4 together denote xe2x80x94CH2xe2x80x94Oxe2x80x94COxe2x80x94; or
(viii) X is O, R1 is cyclobutyl, R2 and R4 are each hydrogen and R3 is xe2x80x94N(CH3)COCH3; or
(ix) X is NH, R1 is cyclopropyl, R2 and R4 are each hydrogen and R3 is 4-methyl-1-piperazinyl; or
(x) X is NH, R1 is tert-butyl, R2 and R4 are each hydrogen and R3is xe2x80x94N(CH3)COCH3; or
(xi) X is NH, R1 is isopropyl, R2 and R4 are each hydrogen and R3 is xe2x80x94N(CH2CH3)COCH3; or
(xii) X is NH, R1 is cyclopropyl, R2 and R4 are each hydrogen and R3 is xe2x80x94N(CH3)COCH2CH3;
the compounds being in free form or in the form of pharmaceutically acceptable salts, particularly hydrochloride or trifluoroacetate salts.
The present invention also provides a process for the preparation of compounds of formula I and their salts which comprises
(A) reacting a compound of formula 
xe2x80x83with a compound of formula 
where X, R1, R2, R3 and R4 are as hereinbefore defined and Y is a leaving group, preferably halogen such as bromine, iodine or, in particular chlorine, a free functional group in the compounds of formulae V and VI other that those involved in the reaction being protected, if necessary, by a removable protecting group; or
(B) for the preparation of a compound of formula I where R2, R3 or R4 is a carboxy or carboxyalkyl group, cleaving a corresponding compound of formula I in which R2, R3 or R4 is an alkoxycarbonyl or alkoxycarbonylalkyl group respectively; or
(C) for the preparation of a compound of formula I where R2, R3 or R4 is an alkoxycarbonyl or alkoxycarbonylalkyl group, appropriately esterifying a corresponding compound of formula I in which R2, R3 or R4 is a carboxy or carboxyalkyl group; or
(D) for the preparation of a compound of formula I where R2, R3 or R4 is a group of formula xe2x80x94SO2N(R11)R12 as hereinbefore defined, appropriately aminating a corresponding compound of formula 
where R1 is as hereinbefore defined and R2a, R3a and R4a are respectively the same as R2, R3 and R4 as hereinbefore defined, with the exception that at least one of them is a group of formula xe2x80x94SO2xe2x80x94Hal, where Hal is halogen, preferably chlorine or bromine; or
(E) for the preparation of a compound of formula I where R2, R3 or R4 is a group of formula xe2x80x94CON(R13)R14 as hereinbefore defined, appropriately aminating a corresponding compound of formula I where R2, R3 or R4 is a carboxy group;
and optionally converting a resultant compound of formula I in protected form into a corresponding compound in unprotected form;
and recovering the resultant compound of formula I in free or salt form.
Protecting groups, their introduction and their removal are described, for example, in xe2x80x9cProtective Groups in Organic Synthesisxe2x80x9d, T. W. Greene et al., John Wiley and Sons Inc, Second Edition, 1991.
Process variant (A) can be carried out using conventional procedures. It is conveniently, carried out in an inert organic solvent, preferably a polar solvent such as dioxan or N-methylpyrrolidone. The reaction temperature is conveniently from 50 to 250xc2x0 C., preferably from 100 to 150xc2x0 C. The reaction may be catalysed by a strong acid, a tertiary base or, preferably, metal ions such as Ag, Cu, Li, Ni, Zn, La, Yb or Sn. The reaction is conveniently carried out using 1 to 5 equivalents, for example 1 to 3 equivalents, of the compound of formula VI, per equivalent of the compound of formula V.
Compounds of formulae V and VI are known or may be prepared by methods analogous to those used for preparation of the known compounds. Thus compounds of formula V may be prepared, for example, as described in WO97/16452 or as described hereinafter in the Examples.
Process variant (B) may be carried out by conventional methods for ester cleavage, for example using conventional acid- or base-catalysed hydrolysis, or analogously as described hereinafter in the Examples.
Process variant (C) may be effected using conventional esterification procedures or analogously as described hereinafter in the Examples.
Process variant (D) may be effected by conventional procedures, for example by reaction of the halosulfonyl compound of formula VII with a compound of formula HN(R11)R12 where R11 and R12 are as hereinbefore defined under known conditions or analogously as described hereinafter in the Examples. Compounds of formula VII are known or may be prepared by methods analogous to those used for the preparation of known compounds, for example by reacting a corresponding compound, which is unsubstituted in the position on the benzene ring where the halosulfonyl group is to be introduced, with a halosulfonating agent such as chlorosulfonic acid, e.g. as described hereinafter in the Examples.
Process variant (E) may be effected by conventional methods, for example by conversion of the corresponding carboxy compound into an acid halide and reacting the acid halide with a compound of formula HN(R13)R14 where R13 and R14 are as hereinbefore defined under known conditions or analogously as described hereinafter in the Examples.
Compounds of formula I in free form may be converted into salt form, and vice versa, in a conventional manner. The compounds in free or salt form can be obtained in the form of hydrates or solvates containing a solvent used for crystallization.
Compounds of formula I can be recovered from the reaction mixture and purified in a conventional manner. Isomer mixtures can be separated into individual isomers, e.g. enantiomers, in a conventional manner, e.g. by fractional crystallization.
Compounds of formula I in free or salt form are useful as pharmaceuticals. Accordingly the invention also provides a compound of formula I in free or pharmaceutically acceptable salt form for use as a pharmaceutical. The compounds of formula I in free or pharmaceutically acceptable salt form, hereinafter referred to alternatively as xe2x80x9cagents of the inventionxe2x80x9d, inhibit the activity of the tyrosine protein kinase syk, which is an activator of pro-inflammatory cells driving an allergic response. This inhibitory property of the agents of the invention can be demonstrated in the following assay:
In this assay the effect of an agent of the invention on the phosphorylation of a peptide by syk kinase is determined. The phosphate is transferred from the terminal phosphate of adenosine triphosphate (ATP) to the biotin-modified peptide biotin-EDPDYEWPSA (available from Genosys) which is a known specific substrate for syk. When 33P-phosphorylated peptide binds to streptavidin-polyvinyltoluene (PVT) Scintillation Proximity Assay (SPA) beads (available from Amersham), the emitted xcex2-particles excite the fluorophore in the beads and produce light. Free 33P-ATP in solution does not excite the fluorophore because the beads are separated from solution by flotation and so it is not in dose proximity to the beads. The scintillation count is therefore a measure of the extent to which the test compound inhibits phosphorylation by syk kinase.
To the wells of an Optiplate (Canberra Packard) are added (i) the compound under test in DMSO/distilled water (10 xcexcl), (ii) 20 xcexcl of a composition formed by mixing 1 mM biotin-EDPDYEWPSA (5.5 xcexcl), 300 xcexcM ATP (18.3 xcexcl), and 33P-ATP in sufficient amount to add 0.1 xcexcCi 33P-ATP per well (1.1 xcexcl on the day of production) and making up the volume to 2.2 ml with a buffer (Buffer A) prepared by dissolving tris-base (0.36 g) in distilled water (80 ml), adjusting the pH to 7.5 with 1M hydrochloric acid, adding 1M aqueous MgCl2 (1.5 ml), 50 mM aqueous sodium orthovanadate (30 xcexcl) and 1M aqueous dithiothrietol (150 xcexcl), and making the volume up to 120 ml with distilled water, (iii) 0.5% w/v syk kinase in Buffer A (20 xcexcl). The plate is incubated at room temperature for 30 minutes with shaking, the reaction is then terminated by addition to all wells of 150 xcexcl of a mixture prepared by reconstituting 500 mg Streptavidin-PVT SPA beads in 373 ml of Tris-buffered saline containing 673.6 g cesium chloride, 20 ml 0.5M EDTA and 27.5 mg ATP (disodium salt) per litre. The plate is again incubated at room temperature for 30 minutes with shaking, then sealed using Top Seal-S (Canberra Packard) according to the manufacturer""s instructions and left to stand at room temperature for 1 hour. The resulting scintillations are counted using a Packard TopCount, each well being counted for 1 minute.
The procedure is repeated for different concentrations of test compound selected to cover the range of 0% to 100% inhibition and the concentration at which 50% inhibition of syk kinase phosphorylation occurs (IC50) for each compound is determined from concentration-inhibition curves in a conventional manner.
The compounds of the Examples hereinbelow have IC50 values of the order of 1 xcexcM or less in the above assay. For instance, the compounds of Examples 1 to 7 hereinbelow have IC50 values of 3 nM, 4 nM, 5 nM, 5 nM, 9 nM, 10 nM and 10 nM respectively, the compounds of Examples 102 to 104 have IC50 values of 5 nM, 2 nM and 3.6 nM respectively and the compunds of Examples 138, 141, 170, 172, 188 and 201 have IC50 values of 14 nM, 4.5 nM, 10 nM, 6 nM, 5 nM and 5 nM respectively.
Having regard to their inhibition of syk kinase, and their suppression of IgE-mediated degranulation of mast cells, the agents of the invention are useful in the treatment of conditions which are mediated by syk kinase, particularly inflammatory or allergic conditions. Treatment in accordance with the invention may be symptomatic or prophylactic.
Accordingly, the agents of the invention are useful in the treatment of inflammatory or obstructive airways diseases. Inflammatory or obstructive airways diseases to which the present invention is applicable include asthma of whatever type or genesis including both intrinsic (non-allergic) asthma and extrinsic (allergic) asthma. Treatment of asthma is also to be understood as embracing treatment of subjects, e.g. of less than 4 or 5 years of age, exhibiting wheezing symptoms and diagnosed or diagnosable as xe2x80x9cwheezy infantsxe2x80x9d, an established patient category of major medical concern and now often identified as incipient or early-phase asthmatics. (For convenience this particular asthmatic condition is referred to as xe2x80x9cwheezy-infant syndromexe2x80x9d.)
Prophylactic efficacy in the treatment of asthma will be evidenced by reduced frequency or severity of symptomatic attack, e.g. of acute asthmatic or bronchoconstrictor attack, improvement in lung function or improved airways hyperreactivity. It may further be evidenced by reduced requirement for other, symptomatic therapy, i.e. therapy for or intended to restrict or abort symptomatic attack when it occurs, for example anti-inflammatory (e.g. corticosteroid) or bronchodilatory. Prophylactic benefit in asthma may in particular be apparent in subjects prone to xe2x80x9cmorning dippingxe2x80x9d. xe2x80x9cMorning dippingxe2x80x9d is a recognised asthmatic syndrome, common to a substantial percentage of asthmatics and characterised by asthma attack, e.g. between the hours of about 4 to 6 am, i.e. at a time normally substantially distant form any previously administered symptomatic asthma therapy.
Other inflammatory or obstructive airways diseases and conditions to which the present invention is applicable include adult respiratory distress syndrome (ARDS), chronic obstructive pulmonary or airways disease (COPD or COAD), including chronic bronchitis or dyspnea associated therewith, emphysema, as well as exacerbation of airways hyperreactivity consequent to other drug therapy, in particular other inhaled drug therapy. The invention is also applicable to the treatment of bronchitis of whatever type or genesis including, e.g., acute, arachidic, catarrhal, croupus, chronic or phthinoid bronchitis. Further inflammatory or obstructive airways diseases to which the present invention is applicable include pneumoconiosis (an inflammatory, commonly occupational, disease of the lungs, frequently accompanied by airways obstruction, whether chronic or acute, and occasioned by repeated inhalation of dusts) of whatever type or genesis, including, for example, aluminosis, anthracosis, asbestosis, chalicosis, ptilosis, siderosis, silicosis, tabacosis and byssinosis.
Having regard to their anti-inflammatory activity, in particular in relation to inhibition of cosinophil activation, agents of the invention are also useful in the treatment of eosinophil related disorders, e.g. cosinophilia, in particular eosinophil related disorders of the airways (e.g. involving morbid eosinophilic infiltration of pulmonary tissues) including hypereosinophilia as it effects the airways and/or lungs as well as, for example, cosinophil-related disorders of the airways consequential or concomitant to Lxc3x6ffler""s syndrome, eosinophilic pneumonia, parasitic (in particular metazoan) infestation (including tropical eosinophilia), bronchopulmonary aspergillosis, polyarteritis nodosa (including Churg-Strauss syndrome), eosinophilic granuloma and eosinophil-related disorders affecting the airways occasioned by drug-reaction.
Agents of the invention are also useful in the treatment of inflammatory or allergic conditions of the skin, for example psoriasis, contact dermatitis, atopic dermatitis, alopecia areata, erythema multiforma, dermatitis herpetiformis, scleroderma, vitiligo, hypersensitivity angiitis, urticaria, bullous pemphigoid, lupus erythematosus, pemphisus, epidermolysis bullosa acquisita, and other inflammatory or allergic conditions of the skin.
Agents of the invention may also be used for the treatment of other diseases or conditions, in particular diseases or conditions having an inflammatory component, for example, treatment of diseases and conditions of the eye such as conjunctivitis, keratoconjunctivitis sicca, and vernal conjunctivitis, diseases affecting the nose including allergic rhinitis, and inflammatory bowel disease such as ulcerative colitis and Crohn""s disease.
The effectiveness of an agent of the invention in inhibiting inflammatory conditions, for example in inflammatory airways diseases, may be demonstrated in an animal model, e.g. a mouse or rat model, of airways inflammation or other inflammatory conditions, for example as described by Szarka et al, J. Immunol. Methods (1997) 202:49-57; Renzi et al, Am. Rev. Respir. Dis. (1993) 148:932-939; Tsuyuki et al., J. Clin. Invest. (1995) 96:2924-2931; and Cemadas et al (1999) Am. J. Respir. Cell Mol. Biol. 20:1-8.
The agents of the invention are also useful as co-therapeutic agents for use in conjunction with anti-inflammatory or bronchodilatory drug substances, particularly in the treatment of obstructive or inflammatory airways diseases such as those mentioned hereinbefore, for example as potentiators of therapeutic activity of such drugs or as a means of reducing required dosaging or potential side effects of such drugs. An agent of the invention may be mixed with the anti-inflammatory or bronchodilatory drug in a fixed pharmaceutical composition or it may be administered separately, before, simultaneously with or after the anti-inflammatory or bronchodilatory drug. Such anti-inflammatory drugs include steroids, in particular glucocorticosteroids such as budesonide, beclamethasone, fluticasone or mometasone, and dopamine receptor agonists such as cabergoline, bromocriptine or ropinirole. Such bronchodilatory drugs include anticholinergic or antimuscarinic agents, in particular ipratropium bromide, oxitropium bromide and tiotropium bromide. Combinations of agents of the invention and steroids may be used, for example, in the treatment of COPD or, particularly, asthma. Combinations of agents of the invention and anticholinergic or antimuscarinic agents or dopamine receptor agonists may be used, for example, in the treatment of asthma or, particularly, COPD.
In accordance with the foregoing, the invention also provides a method for the treatment of a condition mediated by syk kinase, for example an inflammatory or allergic condition, particularly an inflammatory or obstructive airways disease, which comprises administering to a subject, particularly a human subject, in need thereof an effective amount of a compound of formula I in a free or pharmaceutically acceptable salt form as hereinbefore described. In another aspect the invention provides a compound of formula I, in free or pharmaceutically acceptable salt form, as hereinbefore described for use in the manufacture of a medicament for the treatment of a condition mediated by syk kinase.
The agents of the invention may be administered by any appropriate route, e.g. orally, for example in the form of a tablet or capsule; parenterally, for example intravenously; by inhalation, for example in the treatment of inflammatory or obstructive airways disease; intranasally, for example in the treatment of allergic rhinitis; topically to the skin, for example in the treatment of atopic dermatitis; or rectally, for example in the treatment of inflammatory bowel disease.
In a further aspect, the invention also provides a pharmaceutical composition comprising a compound of formula I in free or pharmaceutically acceptable salt form together with a pharmaceutically acceptable diluent or carrier therefor. The composition may contain a co-therapeutic agent such as an anti-inflammatory or bronchodilatory drug as hereinbefore described. Such compositions may be prepared using conventional diluents or excipients and techniques known in the galenic art. Thus oral dosage forms may include tablets and capsules. Formulations for topical administration may take the form of creams, ointments, gels or transdermal delivery systems, e.g. patches. Compositions for inhalation may comprise aerosol or other atomizable formulations or dry powder formulations.
The invention includes (A) an agent of the invention in inhalable form, e.g. in an aerosol or other atomisable composition or in inhalable particulate, e.g. micronised form, (B) an inhalable medicament comprising an agent of the invention in inhalable form; (C) a pharmaceutical product comprising such an agent of the invention in inhalablc form in association with an inhalation device; and (D) an inhalation device containing an agent of the invention in inhalable form.
Dosages of agents of the invention employed in practising the present invention will of course vary depending, for example, on the particular condition to be treated, the effect desired and the mode of administration. In general, suitable daily dosages for administration by inhalation are of the order of 0.1 to 100 mg/kg while for oral administration suitable daily doses are of the order of 1 to 1000 mg/kg.